tbuckley/cabot-search huggingface dataset:
Abstract 6394: The SB Image Processing Toolkit: Machine learning for cancer research on the CGC
Authors: Soner Koc, Jovana Babic, Nevena Nikolic, Ana Stankovic, Daniel Ventre, Manisha Ray, Zelia F. Worman, Sai Lakshmi Subramanian, Dennis A. Dean, Jack DiGiovanna, Brandi Davis Dusenbery
Journal: Cancer Research (2022)

Abstract Applying machine learning algorithms to analysis of multi-omics datasets has provided a wealth of analysis and interpretations of data not easily achievable by conventional methods. The Cancer Genomics Cloud (CGC), powered by Seven Bridges, offers many helpful features to simplify and streamline the performance of machine learning (ML) tasks on the platform. The CGC platform contains features and tools for all of the steps of a ML project, from data exploration, to model generation, to production, so that all key steps occur on the platform. The Data Cruncher interactive analysis tool enables users to perform data exploration, modeling, training, and visualization using familiar frameworks like Jupyterlab and RStudio. We applied this ML methodology to imaging tools, to create The SB Image Processing Toolkit. Here we demonstrate the use of this toolkit with specific cancer datasets, including training and analysis, with all steps taking place on the cloud. The SB Image Processing Toolkit is a collection of various deep-learning, preprocessing, and utility tools and workflows created with the purpose of performing image class prediction on any type of image data. The toolkit supports a variety of images used in cancer research, such as histopathology and radiology images, and common formats like JPG or PNG. There are nine distinct tools within the toolkit, including methods for quality control, normalization, preprocessing for histopathology or radiology images, classification, and deep learning. Together, these tools create an easy-to-use infrastructure to enable various stages of ML and Image Processing. Most importantly, it was designed to enable users to create and use ML image classifiers on the CGC without any coding experience. All workflows can be searched for and implemented via the Public Apps Gallery on the CGC. Users can import image data, run analysis, and compare results all in one environment. By harnessing the scale and flexibility of cloud computing, the SB Image Processing Toolkit brings massive speed and price improvements compared to manual writing and running model training scripts. In conjunction with the access to data and ease of use, the CGC makes complex machine learning methods accessible to any researcher. Citation Format: Soner Koc, Jovana Babic, Nevena Nikolic, Ana Stankovic, Daniel Ventre, Manisha Ray, Zelia F. Worman, Sai Lakshmi Subramanian, Dennis A. Dean, Jack DiGiovanna, Brandi Davis Dusenbery. The SB Image Processing Toolkit: Machine learning for cancer research on the CGC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6394.
Impact of COVID-19 pandemic on asthma exacerbations: Retrospective cohort study of over 500,000 patients in a national English primary care database
Authors: Syed Ahmar Shah, Jennifer K. Quint, Aziz Sheikh
Journal: The Lancet Regional Health - Europe (2022)

Several countries reported a substantial reduction in asthma exacerbations associated with COVID-19 pandemic-related restrictions. However, it is not known if these early reported declines were short-term and if these have rebounded to pre-pandemic levels following easing of lockdown restrictions.
Abstract 4235: PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma models
Authors: Mykola Zdioruk, Michal Nowicki, Bin Wu, Paul Boucher, Yuji Takeda, Weiyi Li, E Antonio Chiocca, Sean E. Lawler
Journal: Cancer Research (2022)

Abstract Introduction: We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine models of the brain tumor glioblastoma. However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Here we examine the efficacy and mechanism of PPRX-1701 in murine glioblastoma models. Methods: In vitro glioblastoma cell proliferation and migration assays were performed using standard approaches. Effects of PPRX-1701 on interferon-γ (IFN γ) signaling were determined by Western blotting. Delivery to murine GBM was assessed using a luminescent reporter assay, and survival studies were performed in immunocompetent murine glioblastoma models. Results: PPRX-1701 effects on glioblastoma cell proliferation and migration were indistinguishable from BiA alone. Our data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p &amp;lt; 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further mechanistic studies have shown that PPRX-1701/BiA blocks the expression of multiple immunosuppressive molecules in GBM downstream of interferon-γ (IFNγ) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. Conclusion: This data supports further development of PPRX-1701 as a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies. Citation Format: Mykola Zdioruk, Michal Nowicki, Bin Wu, Paul Boucher, Yuji Takeda, Weiyi Li, E Antonio Chiocca, Sean E. Lawler. PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4235.
Abstract 2157: SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities
Authors: Feng Zhou, Guimei Yang, Feng Tang, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang
Journal: Cancer Research (2022)

Abstract Protein arginine methyltransferase 5 (PRMT5) is observed dysregulation in both solid and hematological tumors. Increasing evidences demonstrated that PRMT5 is a potential therapeutic target. Given the essential role in maintenance of adult hematopoietic cells, inhibition of PRMT5 leads to hematological toxicity. Anemia is the most common treatment related adverse event observed by PRMT5 inhibitor, such as GSK3326595, which limited the dose escalation. Therefore, developing a PRMT5 inhibitor with tumor-biased distribution could be an effective approach to avoid these target related toxicities. In this study, a novel and high selective PRMT5 inhibitor, SCR-6277 was identified. SCR-6277 inhibited the PRMT5 enzyme with an IC50 of 1.5 nM, and showed a high selectivity against other five methyltransferase isoforms (selectivity folds &amp;gt;1000). SCR-6277 potently inhibited the PRMT5-mediated SDMA production in Z-138 cells (IC50, 0.6 nM) and the cell proliferation (IC50, 3 nM). SCR-6277 also demonstrated robustly anti-proliferation activities on multiple PRMT5 proficient solid tumor cell lines (IC50 values ranging from 20 - 130 nM) and no inhibitory effects on PRMT5 deficient cell lines. SCR-6277 had good oral bioavailability and favorable pharmacokinetic properties. In Z-138 and 5637 xenograft models, SCR-6277 robustly inhibited tumor growth. In contrast to GSK3326595, SCR-6277 showed tumor biased distribution. Exposure of SCR-6277 in tumors were 50 folds higher than that in plasma. The extremely high T/P ratio made SCR-6277 achieve the better anti-tumor activities at lower blood exposure (Table 1). In conclusion, SCR-6277 is a novel, potent and high selective PRMT5 inhibitor. And higher tumor/plasma distribution ratio predicts SCR-6277 is a more tolerant and effective PRMT5 inhibitor in human. Table 1. Distribution and anti-tumor activity of SCR-6277 Dose TGI Plasma Conc. (ng/mL) * Tumor Conc. (ng/g) * T/P ratio GSK3326595 50 mpk,BID 87% 45 106 2 SCR-6277 15 mpk,BID 117% 20 668 50 Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2157.
Abstract 2847: Simultaneous TCR and transcriptomic sequencing of single Tcells defines biological subtypes in pancreatic cancer for adoptive Tcell therapy
Authors: Aislyn Schalck, Donastas Sakellariou-Thompson, Marie-Andrée Forget, Emi Sei, Tara Hughes, Shanshan Bai, Min Hu, Tapsi Kumar, Mark Hurd, Matthew Katz, Chine-Wei Tzeng, Shubham Pant, Milind Javle, Anirban Maitra, Cara Haymaker, Michael Kim, Nicholas Navin, Chantale Bernatchez
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal tumor-type with very few effective treatment strategies. Attempts to improve outcomes using immune checkpoint blockade therapy have also failed, likely because the overall Tcell infiltration in this tumor-type is low. Despite this, the presence of CD3+CD8+ tumor-infiltrating lymphocytes (TIL) in PDAC is associated with improved survival outcomes, suggesting that other immune-based strategies could be more successful. Here, we examine ex vivo tumor-infiltrating Tcell expansion for adoptive Tcell therapy (ACT) as a potential strategy for treating PDAC. The focus of this study is to understand the transcriptional states of Tcells in the pancreas and PDACs and how they change with ex vivo expansion and re-infusion into patients as treatment strategy. We have performed both single cell transcriptome and TCR sequencing (scRNA-TCRseq) on 54,579 Tcells from 8 human PDAC samples and the ex vivo grown TIL from a subset of 6 patients and found 13 purported substates. Through TCR tracking of the Tcell clonotypes, we find that the expansion protocol is able to expand Tcells found in many different Tcell states in the primary tumor. Furthermore, we compared our thirteen tumor-infiltrating substates with 41,935 Tcells from two other independent single cell studies across 71 samples, and confirmed our substates to be present across all datasets. Citation Format: Aislyn Schalck, Donastas Sakellariou-Thompson, Marie-Andrée Forget, Emi Sei, Tara Hughes, Shanshan Bai, Min Hu, Tapsi Kumar, Mark Hurd, Matthew Katz, Chine-Wei Tzeng, Shubham Pant, Milind Javle, Anirban Maitra, Cara Haymaker, Michael Kim, Nicholas Navin, Chantale Bernatchez. Simultaneous TCR and transcriptomic sequencing of single Tcells defines biological subtypes in pancreatic cancer for adoptive Tcell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2847.
Abstract ND11: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers
Authors: Hans Purkey
Journal: Cancer Research (2022)

Abstract Mutations in KRAS are the most common oncogenic driver mutations in human cancers. The KRAS G12C mutation is one of the most prevalent KRAS mutations, present in approximately 12% of non-small cell lung cancer, 4% of colorectal cancer, and up to 4% of other cancer types. The recent discovery and development of covalent KRAS G12C inhibitors provides an opportunity to inhibit what has historically been considered to be an “undruggable” target. GDC-6036 is an orally bioavailable, highly potent and selective KRAS G12C inhibitor, with a median IC50 in the sub-nanomolar range and greater than 18,000-fold selectivity for G12C versus non-G12C cell lines. GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will highlight the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development. Citation Format: Hans Purkey. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND11.
Abstract 4107: Discovery and preclinical evaluation of <i>VRTX126</i>, a novel, highly selective and potent KRASG12Cinhibitor
Authors: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar
Journal: Cancer Research (2022)

Abstract KRASG12C is an important oncogenic driver mutation and occurs in about 13% of NSCLC and 1-3% of colorectal and other solid tumors. Lumakras࣪ (sotorasib), a KRASG12C inhibitor was recently approved for treatment of NSCLC, and others, such as, Adagrasib have shown relatively modest activity for KRASG12C.This modest activity may be partly due to incomplete target occupancy or due to unavailability of the drug at the target site, to elicit maximum clinical response. Clearly, this gives path for development of inhibitors which are potent, but also have desired drug like properties to achieve maximal clinical benefit in patients harboring KRASG12C mutation. Here, we report the identification of VRTX126, a novel, highly selective and potent inhibitor of the KRASG12C, discovered using fragment-based drug design. VRTX126 exhibited an IC50 of 10 nM in H358. VRTX126 also inhibited phospho-ERK with an IC50 of &amp;lt;20 nM and &amp;lt;10 nM in H358 and Mia-Paca-2 cell lines respectively, while demonstrating multi fold selectivity over KRAS wild-type or nonG12C mutant cells lines. In xenograft model harboring KRASG12C mutation, VRTX126 exhibited tumor growth inhibition at therapeutically relevant doses. Combination strategies with other targeted therapies such as, our proprietary SOS1 inhibitor, and other marketed or available MEK1/2, SHP2 inhibitors targeting Ras/Raf/MEK pathway is being explored. VRTX126 showed favourable oral properties with dose proportional pharmacokinetics. VRTX126 was found to have no adverse effect on hERG (10 uM). Additionally, early evaluation in acute (&amp;gt;1 g/kg (p.o.) and &amp;gt;0.2 g/kg (i.v.) was well tolerated, with no elevation in liver enzymes and repeat does studies indicated good safety margins, thus supporting further evaluation of VRTX126 in IND enabling studies. A first-in-human Phase 1 clinical study in KRASG12C mutated patients of NSCLC and mCRC will be planned upon completion of through safety evaluations. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar. Discovery and preclinical evaluation of VRTX126, a novel, highly selective and potent KRASG12Cinhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4107.
Abstract 964: Tumor cell plasticity promotes metastasis across heterogeneous tumors
Authors: Juliane Winkler, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, Zena Werb
Journal: Cancer Research (2022)

Abstract Metastasis, the growth of secondary tumors in distant organs, is the major cause of cancer-related deaths due to insufficient therapeutic effects of conventional treatment. Individual tumor cells exhibit heterogeneous features and growth potentials within the same tumor that may influence metastasis formation. During the metastatic cascade, tumor cells adapt their phenotype to various microenvironments that are distinct from their original site resulting in heterogeneous metastatic cells that often are resistant to conventional treatment. The underlying mechanisms of why some tumor cells can give rise to metastases, whereas others cannot are remarkably poorly understood. We established patient-derived xenograft (PDX) models of breast cancer with different metastatic potential and preserved tumor heterogeneity. We analyzed the intrinsic cellular programs of individual tumor cells that influence the metastatic potential of breast cancers using different single-cell RNA-sequencing protocols (MULTI-Seq and Smart-Seq2). Using gene expression profiling of matched primary tumor and metastatic cells of 13 human breast cancers, we demonstrated that while human tumors showed profound inter-patient heterogeneity, they also shared signatures of differentially expressed genes between primary tumor and metastatic cells. Tumors with similar metastatic capabilities shared similar signatures, suggesting potential targets to directly treat metastasis. Additionally, we found that the plasticity of tumor cells is a common feature across tumors that is beneficial for the formation of metastasis. Tumors with higher levels of plastic tumor cells have a greater ability to form metastases. Moreover, we identified a subset of tumor cells expressing both markers of epithelial and mesenchymal characteristics, demonstrating in-vivo evidence for tumor epithelial-mesenchymal plasticity (EMP) in the metastatic cascade. The EMP is a continuum of states with epithelial and mesenchymal cell states as the two extremes of this continuum. The identified transition cells express distinct markers suggesting that these cells may represent a novel and overlooked cell type within the EMP continuum. Given the importance of tumor plasticity in the metastatic cascade, inhibiting the subset of tumor cells that are currently undergoing EMP may represent a novel treatment strategy for metastasis. Citation Format: Juliane Winkler, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, Zena Werb. Tumor cell plasticity promotes metastasis across heterogeneous tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 964.
Abstract 5712: Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception
Authors: Sabeeta Kapoor, Roderick H. Dashwood
Journal: Cancer Research (2022)

Abstract Introduction Epigenetic mechanisms play an important role in the initiation and advancement of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions1,2. We examined compounds from natural sources as BRD7/9 inhibitors, seeking lead candidates outside of the widely studied bromodomain and extraterminal (BET) family3. Methods As reported4,5, docking in silico involved STRAP and AutoDock Vina, ligand-protein interactions employed PDBePISA and LPC/CSU, and BROMOscan®-Bromodomain arrays were used to screen for BRD7/9 interacting compounds. BRD7/9 inhibitors also were assessed by isothermal titration calorimetry (ITC) and by anticancer activities in human colon cancer cells. Results Docking in silico identified several dietary polyphenols as potential BRD7/9 inhibitors, with binding energies ≤ -8.0 kcal/mol. BROMOscan® and ITC experiments prioritized aspalathin, orientin, epigallocatechin-3-gallate, quercetin and equol for further investigation. Treatment with selected polyphenols mimicked BRD7/9 siRNA-mediated knockdown in reducing colon cancer cell viability and inhibiting colony formation, leading to DNA damage and apoptosis induction. Normal colonic epithelial cells were unaffected by the treatments, signifying cancer-specific targeting. These findings suggest that dietary polyphenols can recognize and target BRD7/9 proteins for potential cancer interception. Acknowledgements Research supported in part by NCI grant CA122959, the John S. Dunn Foundation, and a Chancellor's Research Initiative.1)Jung G et al., Nat Rev Gastroenterol Hepatol 2020;17:111-130. 2)Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 2017;18:246-262.3)Damiani E et al., J Cancer Prev 2020;25:189-203. 4)Rajendran P et al., Cancer Res 2019;79:918-927. 5)Kapoor S et al., Cancers (Basel) 2021;13:1438. Citation Format: Sabeeta Kapoor, Roderick H. Dashwood. Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5712.
Abstract 2096: Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer
Authors: McKenzie Crist, Maria Lehn, Vinita Takiar, Trisha Wise-Draper
Journal: Cancer Research (2022)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer in the world, yet 5 year survival remains poor for those with recurrence despite advances in treatment such as immunotherapy. Checkpoint blockade substantially improved survival in ~20% of recurrent and/or metastatic HNSCC patients. However, given the lack of efficacy in most patients, and the known immunosuppressive nature of HNSCC, exploring other potential immune cell therapeutic targets is of interest. Decreased natural killer (NK) as well as increased immunosuppressive CD4+ regulatory T cells (Tregs) in both peripheral blood and the tumor microenvironment are associated with a poor prognosis in HNSCC. We discovered that the anti-diabetes drug, metformin, which is also known to improve immune cell function, not only increases peripheral NK cells in HNSCC patients to the level of healthy controls, but also suppresses IL-9 secretion from NK cells. IL-9 has been implicated as a driving factor in allergic disease, a poor prognosis factor in hematologic malignancies, and an enhancer of T-reg immunosuppressive abilities. However, the function of IL-9 in solid tumors is poorly understood. Interestingly, upon depletion of CD56+ NK and NKT cells from peripheral blood mononuclear cells (PBMCs), there was a significant increase of IL-9 secretion. This effect was negated upon depletion of CD4+ T cells suggesting that NK cells may directly or indirectly inhibit CD4+ T cell IL-9 production. In order to understand potential consequences of IL-9 overproduction, we subjected HNSCC cell lines, which we demonstrated express IL9 receptor, to exogenous IL-9 which resulted in enhanced proliferation. We also found that IL-9 plasma levels are high in HNSCC patients compared to healthy controls corroborating a potential tumorigenic role for IL-9. In order to elucidate potential mechanism(s) by which NK/NKT cells regulate CD4+ T cell production, we performed single-cell RNAseq on PBMCs upon NK and NKT cell depletion. We also performed flow cytometry to identify specific CD4+ cell types responsible for increased IL-9 production and the consequential changes in other immune cell phenotypes upon the absence of NK/NKT cells. Understanding the role of IL-9 in HNSCC will be important for utilizing IL-9 as a potential marker for HNSCC prognosis as well as a possible target for future immunotherapy approaches. Citation Format: McKenzie Crist, Maria Lehn, Vinita Takiar, Trisha Wise-Draper. Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2096.